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Studies have shown pathogenic variants in more than 20 different genes as causative for childhood-onset primary osteoporosis. The X-chromosomal <jats:italic>PLS3<\/jats:italic>, encoding Plastin-3, is one of the more recently identified genes. In this study, we describe five new families from four different European countries with <jats:italic>PLS3<\/jats:italic>-related skeletal fragility. The index cases were all hemizygous males presenting with long bone and vertebral body compression fractures. All patients had low lumbar spine bone mineral density (BMD). The age at the first clinical fracture ranged from 1.5 to 13&amp;nbsp;years old. Three of the identified <jats:italic>PLS3<\/jats:italic> variants were stop-gain variants and two were deletions involving either a part or all exons of the gene. In four families the variant was inherited from the mother. All heterozygous women reported here had normal BMD and no bone fractures. Four patients received bisphosphonate treatment with good results, showing a lumbar spine BMD increment and vertebral body reshaping after 10\u00a0months to 2\u00a0years of treatment. Our findings expand the genetic spectrum of <jats:italic>PLS3<\/jats:italic>-related osteoporosis. Our report also shows that early treatment with bisphosphonates may influence the disease course and reduce the progression of osteoporosis, highlighting the importance of early diagnosis for prompt intervention and appropriate genetic counseling.<\/jats:p>","DOI":"10.1007\/s00223-023-01162-4","type":"journal-article","created":{"date-parts":[[2023,12,3]],"date-time":"2023-12-03T11:01:56Z","timestamp":1701601316000},"page":"157-170","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["PLS3 Mutations in X-Linked Osteoporosis: Clinical and Genetic Features in Five New Families"],"prefix":"10.1007","volume":"114","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1386-2377","authenticated-orcid":false,"given":"Adriana","family":"Costa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0328-5499","authenticated-orcid":false,"given":"Andreia","family":"Martins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8817-4117","authenticated-orcid":false,"given":"Catarina","family":"Machado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6010-351X","authenticated-orcid":false,"given":"Elena","family":"Lundberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9986-8138","authenticated-orcid":false,"given":"Ola","family":"Nilsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Costantini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8301-324X","authenticated-orcid":false,"given":"Symeon","family":"Tournis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9908-2066","authenticated-orcid":false,"given":"Jakob","family":"H\u00f6ppner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1793-4603","authenticated-orcid":false,"given":"Corinna","family":"Grasemann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4547-001X","authenticated-orcid":false,"given":"Outi","family":"M\u00e4kitie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,12,3]]},"reference":[{"issue":"16","key":"1162_CR1","doi-asserted-by":"publisher","first-page":"1529","DOI":"10.1056\/NEJMoa1308223","volume":"369","author":"FS van Dijk","year":"2013","unstructured":"van Dijk FS, Zillikens MC, Micha D, Riessland M, Marcelis CL, de Die-Smulders CE, Milbradt J, Franken AA, Harsevoort AJ, Lichtenbelt KD, Pruijs HE, Rubio-Gozalbo ME, Zwertbroek R, Moutaouakil Y, Egthuijsen J, Hammerschmidt M, Bijman R, Semeins CM, Bakker AD, Everts V, Klein-Nulend J, Campos-Obando N, Hofman A, te Meerman GJ, Verkerk AJ, Uitterlinden AG, Maugeri A, Sistermans EA, Waisfisz Q, Meijers-Heijboer H, Wirth B, Simon ME, Pals G (2013) PLS3 mutations in X-linked osteoporosis with fractures. 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No research animals were involved in the study.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Human and Animal Rights"}}]}}